Synthetic Studies of the Zoanthamine Alkaloids: Total Synthesis of Zoanthenol Based on an Isoaromatization Strategy

The total synthesis of zoanthenol, a unique aromatic member of the zoanthamine alkaloids, which has exhibited potent anti‐platelet activities on human platelet aggregation, is described in full detail. The key step involves a Brønsted acid‐promoted isoaromatization in the AB ring system to install the crucial aromatic ring. We have not only succeeded in the first total synthesis of zoanthenol, but also established an alternative efficient synthetic route from the commercially available norzoanthamine hydrochloride to zoanthenol.     

Concise Total Synthesis of Dehaloperophoramidine

Perophoramidine, dehaloperophoramidine, and communesin F are structurally related alkaloids having intriguing polycyclic structures. A strategy for the synthesis of dehaloperophoramidine has been developed. In this synthesis all skeletal atoms and all functional groups required to reach the target molecule are incorporated early in the sequence. This approach led to the discovery of two novel substrate‐specific domino processes, one encompassing four steps and the other comprising five steps, thus resulting in an eight‐step synthesis of dehaloperophoramidine.     

Total Synthesis of (±)-Corymine

The first total synthesis of the hexacyclic indole alkaloid (±)-corymine is described. Starting from the readily available N-protected tryptamine, the title compound was achieved in 21 steps in 3.4 % overall yield. Key steps of the synthesis include: a) the addition of a malonate to a 3-bromooxindole to afford 3,3-disubstituted oxindole, b) the formation of a 12-membered cyclic enol ether by intramolecular O-propargylation, immediately followed by propargyl Claisen rearrangement to provide the α-allenyl ketone stereospecifically, c) DMDO oxidation to install a hydroxy group in a highly stereoselective manner, and d) the SmI₂-mediated reductive C−O bond cleavage to remove the α-keto carboxyl group.     

Total Synthesis of (±)‐Strictamine

The total synthesis of strictamine has been achieved in nine steps from a known enol triflate. Characteristic features of our approach included: a) creation of a C7 all‐carbon quaternary stereocenter at an early synthetic stage; b) use of an N,N‐dimethyl tertiary amine as a surrogate of the primary amine for the rapid build‐up of a functionalized 2‐azabicyclo[3,3,1]nonan‐9‐one skeleton (achieved by using a reaction sequence of α‐bromination of the ketone, followed by a stereoconvergent intramolecular nucleophilic substitution reaction); and c) a late‐stage construction of the indolenine unit.     

Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso-Cyclization

We report herein a nonbiomimetic strategy for the total synthesis of the plicamine-type alkaloids zephycarinatines C and D. The key feature of the synthesis is a stereoselective reductive radical ipso-cyclization using visible-light-mediated photoredox catalysis. This cyclization enabled the construction of a 6,6-spirocyclic core structure through the addition of a carbon-centered radical onto the aromatic ring. Biological evaluation of zephycarinatines and their derivatives revealed that the synthetic derivative with a keto group displays moderate inhibitory activity against LPS-induced NO production. This approach could offer future opportunities to expand the chemical diversity of plicamine-type alkaloids as well as providing useful intermediates for their syntheses.     

An Enantioselective Total Synthesis of (−)‐Isoschizogamine

A concise enantioselective total synthesis of (?)‐isoschizogamine, a complex bridged polycyclic monoterpene indole alkaloid, was accomplished. N‐Alkylation of an enantio‐enriched imine with an alkyl iodide afforded an iminium salt, which, upon heating by microwave irradiation in the presence of pivalic acid, was converted into the hexacyclic structure of natural product by a complex but ordered domino sequence. The one‐pot process leading to the formation of one C? C bond and three C? N bonds created three rings and three contiguous stereogenic centers with complete control of both the relative and absolute stereochemistry.     

A Flexible Approach to Grandisine Alkaloids: Total Synthesis of Grandisines B,D, and F

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human δ‐opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4‐addition of ammonia to 9 . Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita–Baylis–Hillman (MBH) reaction via the N‐acyl iminium ion.     

Cascade Reactions: A Driving Force in Akuammiline Alkaloid Total Synthesis

The akuammiline alkaloids are a family of intricate natural products which have received considerable attention from scientists worldwide. Despite the fact that many members of this alkaloid class were discovered over 50 years ago, synthetic chemistry has been unable to address their architectures until recently. This minireview provides a brief overview of the rich history of the akuammiline alkaloids, including their isolation, structural features, biological activity, and proposed biosyntheses. Furthermore, several recently completed total syntheses are discussed in detail. These examples not only serve to highlight modern achievements in alkaloid total synthesis, but also demonstrate how the molecular scaffolds of the akuammilines have provided inspiration for the discovery and implementation of innovative cascade reactions for the rapid assembly of complex structures.     

Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum

Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B‐type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1‐aza‐perhydrocyclopentalene core, representing rings A and E of all calyciphylline B‐type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4‐conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2‐carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines.     

A Historical Review of the Total Synthesis of Natural Products Developed in Portugal

Total synthesis of natural products is an important discipline of organic chemistry that has enabled the development of new synthetic methods and strategies for the preparation and study of the structure and reactivity of complex naturally occurring products. In this review we summarize the synthetic strategies developed in Portugal by several research groups for the synthesis of bioactive natural products including alkaloids, cyclitols, fatty alcohols, phenylpropanoic acids, γ-butyrolactones, xanthones and nucleosides.     

Organocatalytic,Asymmetric Total Synthesis of (−)‐Haliclonin A

The first total synthesis of the alkaloid (?)‐haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3‐alkenyl cyclohex‐2‐enone to set the stereochemistry of the all‐carbon quaternary stereogenic center. The synthesis also features a Pd‐promoted cyclization to form the 3‐azabicyclo[3,3,1]nonane core, a SmI₂‐mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.     

Total Synthesis of (±)‐Alstoscholarisine A

The first total synthesis of the neuroactive indole alkaloid (±)‐alstoscholarisine A is reported. The key step of the concise synthesis is an efficient domino sequence that was used to assemble the 2,8‐diazabicyclo[3.3.1]nonane core through the formation of two C?N bonds and one C?C bond in a single step.     

Total Synthesis of Notoamides F,I, and R and Sclerotiamide

The total synthesis of the natural indole alkaloids (+)‐notoamide F, I, and R and (?)‐sclerotiamide is described. The four heptacyclic compounds were synthesized in 10–12 steps in a convergent and highly stereoselective manner from the readily available Seebach acetal. Key steps of the synthesis include a stereoselective oxidative aza‐Prins cyclization to construct the bicyclo[2.2.2]diazaoctane, and a cobalt‐catalyzed radical cycloisomerization to create the cyclohexenyl ring.